Age-dependent, polyclonal hyperactivation of T cells is reduced in TNF-negative gld/gld mice.
The generalized lymphoproliferative disorder (gld) mouse strain is characterized by severe splenomegaly/lymphadenopathy, the production of autoimmune antibodies, and the appearance of CD4/CD8-negative T cells. An additional TNF deficiency of gld/gld mice attenuates the course of the disorder through a yet-unknown mechanism. In this study, we could demonstrate that the reduced splenomegaly and lymphadenopathy in B6.gld/gld.TNF-/- mice were correlated with a decreased peripheral T cell proliferation rate and a delayed polyclonal activation. A comparative analysis of naïve T cells and memory/effector T cells showed an age-dependent difference in the T cell activation pattern in the spleen of B6.gld/gld and B6.gld/gld.TNF-/- mice. T cells from B6.gld/gld.TNF-/- spleens and lymph nodes showed significantly higher levels of CCR7 and CD62 ligand on their surface compared with B6.gld/gld mice when mice of the same age were compared. Additionally, we found an increased titer of the Th1 cytokine IFN-gamma in the serum of B6.gld/gld mice, whereas the concentration of IFN-gamma was markedly reduced in the serum of B6.gld/gld.TNF-/- mice. These findings support the hypothesis that increased T cell activation and proliferation in the presence of TNF contribute to the exacerbation of the gld syndrome.
Wiede
Florian
F
Comparative Genomics Centre, School of Veterinary and Biomedical Science/School of Pharmacy and Molecular Sciences, Molecular Sciences Bldg. 21, James Cook University, Townsville, Qld 4811, Australia.
Roomberg
Alicia
A
Cretney
Erika
E
Lechner
Anja
A
Fromm
Phillip
P
Wren
Leia
L
Smyth
Mark J
MJ
Körner
Heinrich
H
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D018960:Hyaluronan Receptors / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood; D019041:L-Selectin / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008206:Lymphatic Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054400:Receptors, CCR7 / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013163:Splenomegaly / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
C515371:Ccr7 protein, mouse; D018960:Hyaluronan Receptors; D054400:Receptors, CCR7; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D007371:Interferon-gamma